This proposal from Washington University is part of a new a new five-year, eight center, Investigator-Initiated Interactive Research Project (IRPG). The overall goal of this IRPG is to study genetic relationships between alcoholism, personality traits and neurophysiological measures of neural disinhibition and elements of addiction to alcohol including quantitative measures of tolerance, sensitivity, withdrawal, craving and loss of control. As a member of the IRPG consortium, we will ascertain and assess families that are informative for candidate gene and genetic linkage genetic studies of alcoholism and related phenotypes. We will also monitor and coordinate the ascertainment of informative families and implement a quality assurance program at all centers. We will genotype families from all sites, maintain a data management facility/repository and conduct linkage and candidate gene studies. Members of our data analysis team will develop and extend the analysis of categorical and quantitative phenotypes to include tests of multilocus hypotheses and the analyses of multiple phenotypes. Genetic linkage and candidate gene studies will be conducted in densely affected, multigenerational families of alcohol dependent probands that are ethnically diverse. A genome wide survey in two waves and candidate gene association studies are planned. The genetic relationships between QTLs for these phenotypes will be studied to test hypotheses of additivity, pleiotropy, allelic heterogeneity and epistatic interaction. A Positron Emission Tomography (PET) study in high and low risk subjects will test GABAergic hypotheses of disinhibition in alcohol dependence.